B7x expression on the bronchial epithelium delays CD4 T cell priming after Mycobacterium tuberculosis infection

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Abstract The priming of CD4 T cell responses after Mycobacterium tuberculosis (Mtb) infection is delayed compared to other pathogens. Although it has been thought that the slow replication rate of the bacteria is responsible for the lag in T cell priming, it is possible that negative regulatory pathways that control inflammation in the lung also contribute to this slow T cell response. Here we show that the orphan co-inhibitory ligand B7x contributes to the delay in T cell priming following Mtb infection. We find that B7x is expressed on bronchiolar epithelial cells, and B7x−/− mice display enhanced bacterial control and survive longer than WT mice after pulmonary Mtb infection. The enhanced resistance of B7x−/− mice to Mtb infection is completely dependent on CD4 T cells, but at day 28 post-infection, the peak of the T cell response, there is little difference in the number or function of Mtb-specific effector CD4 T cells. Instead, we find that Mtb-specific CD4 T cells are primed in the mediastinal lymph nodes (mLNs) and accumulate in the lungs much earlier in B7x−/− mice compared to WT mice. B7x blockade is also able to enhance Mtb-specific T cell priming even after inoculation of non-replicating irradiated Mtb into the lungs. Moreover, after ESAT-6/CpG lung immunization, B7x blockade reduces the amount of adjuvant needed to drive T cell expansion in the mLNs by ~50 fold. Collectively, our results indicate the expression of the immune checkpoint molecule B7x by the bronchial epithelium contributes in part to the notorious lag in CD4 T cell responses during tuberculosis by increasing the threshold of innate stimuli needed for the induction of T cell priming.